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Entropic stabilization of the folded states of RNA due to macromolecular crowding.

ABSTRACT: We review the effects of macromolecular crowding on the folding of RNA by considering the simplest scenario when excluded volume interactions between crowding particles and RNA dominate. Using human telomerase enzyme as an example, we discuss how crowding can alter the equilibrium between pseudoknot and hairpin states of the same RNA molecule-a key aspect of crowder-RNA interactions. We summarize data showing that the crowding effect is significant only if the size of the spherical crowding particle is smaller than the radius of gyration of the RNA in the absence of crowding particles. The implication for function of the wild type and mutants of human telomerase is outlined by using a relationship between enzyme activity and its conformational equilibrium. In addition, we discuss the interplay between macromolecular crowding and ionic strength of the RNA buffer. Finally, we briefly review recent experiments which illustrate the connection between excluded volume due to macromolecular crowding and the thermodynamics of RNA folding.

SUBMITTER: Denesyuk NA

PROVIDER: S-EPMC5425724 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Entropic stabilization of the folded states of RNA due to macromolecular crowding.

Denesyuk Natalia A NA Thirumalai D D

Biophysical reviews 20130418 2

We review the effects of macromolecular crowding on the folding of RNA by considering the simplest scenario when excluded volume interactions between crowding particles and RNA dominate. Using human telomerase enzyme as an example, we discuss how crowding can alter the equilibrium between pseudoknot and hairpin states of the same RNA molecule-a key aspect of crowder-RNA interactions. We summarize data showing that the crowding effect is significant only if the size of the spherical crowding part ...[more]

PMID: 28510164

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Project description:The osmolyte trimethylamine N-oxide (TMAO) accumulates in the cell in response to osmotic stress and increases the thermodynamic stability of folded proteins. To understand the mechanism of TMAO induced stabilization of folded protein states, we systematically investigated the action of TMAO on several model dipeptides (leucine, L(2), serine, S(2), glutamine, Q(2), lysine, K(2), and glycine, G(2)) in order to elucidate the effect of residue-specific TMAO interactions on small fragments of solvent-exposed conformations of the denatured states of proteins. We find that TMAO preferentially hydrogen bonds with the exposed dipeptide backbone but generally not with nonpolar or polar side chains. However, interactions with the positively charged Lys are substantially greater than with the backbone. The dipeptide G(2) is a useful model of the pure amide backbone; interacts with TMAO by forming a hydrogen bond between the amide nitrogen and the oxygen in TMAO. In contrast, TMAO is depleted from the protein backbone in the hexapeptide G(6), which shows that the length of the polypeptide chain is relevant in aqueous TMAO solutions. These simulations lead to the hypothesis that TMAO-induced stabilization of proteins and peptides is a consequence of depletion of the solute from the protein surface provided intramolecular interactions are more favorable than those between TMAO and the backbone. To test our hypothesis, we performed additional simulations of the action of TMAO on an intrinsically disordered Aβ(16-22) (KLVFFAE) monomer. In the absence of TMAO, Aβ(16-22) is a disordered random coil. However, in aqueous TMAO solution, Aβ(16-22) monomer samples compact conformations. A transition from random coil to α-helical secondary structure is observed at high TMAO concentrations. The coil to α-helix transition is highly cooperative especially considering the small number of residues in Aβ(16-22). Our work highlights the potential similarities between the action of TMAO on long polypeptide chains and entropic stabilization of proteins in a crowded environment due to excluded volume interactions. In this sense, the chemical chaperone TMAO is a nanocrowding particle.

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Entropic stabilization of the folded states of RNA due to macromolecular crowding.

Publications

Entropic stabilization of the folded states of RNA due to macromolecular crowding.

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